Valsartan, the generic name for N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-valine (denoted as formula I below) is a well known nonpeptide angiotensin II AT1-receptor antagonist and is on the market as Diovan or Tareg for the treatment of hypertension.
According to U.S. Pat. No. 5,399,578 and Bioorganic & Medicinal Chemistry Letters, vol. 4, No. 1, pp. 29-34, 1994, valsartan is prepared by the following reaction steps.
L-valine methyl ester hydrochoride is N-alkylated with 4-bromomethyl-2′-cyanobiphenyl, the product 4-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester thus formed is N-acylated with valeryl chloride to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester. N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester is treated with tributyltin azide to give valsartan methyl ester, which is then hydrolyzed under alkaline condition to give finally valsartan.
4-[(2′-Cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester may also be prepared by reductive amination of 2′-cyanobiphenyl-4-carbaldehyde with L-valine methyl ester using sodium cyanoborohydride.
The above process requires chromatographic techniques to isolate/purify the intermediates, particularly those that are formed in N-alkylation, N-acylation and tetrazole formation steps.
Since it requires chromatographic separations in many stages, the above process is complicated in operation and large-scale equipment is required, which results in poor productivity. In view of these drawbacks, the above process can hardly be said to be an advantageous one from the industrial production viewpoint.
According to U.S. Pat. No. 5,399,578 and Bioorganic & Medicinal Chemistry Letters, vol. 4, No. 1, pp. 29-34, 1994, valsartan is also prepared by the following reaction steps.
L-valine benzyl ester hydrochoride is N-alkylated with 4-bromomethyl-2′-cyanobiphenyl, the product 4-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester so formed is N-acylated with valeryl chloride to give N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester. N-[(2′-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine benzyl ester is treated with tributyltin azide to give valsartan benzyl ester. Valsartan benzyl ester is subjected to catalytic hydrogenation using for example palladium-charcoal as catalyst to give valsartan.
Even though no chromatographic separations are required, the process just mentioned above, too, can hardly be said to be advantageous from the viewpoint of economy because of the use of costly hydrogenating catalysts like palladium-charcoal.
The processes described in the prior art are represented in the scheme shown below.
Thus, there is a need to develop a simple method for economically preparing valsartan and a pharmaceutically acceptable salt thereof having high quality with high yield in a commercial scale.
Debenzylation of a benzyl ester is usually effected by catalytic hydrogenation of the benzyl ester, preferred catalyst being palladium-charcoal.
Surprisingly, we have discovered that substituted or unsubstituted phenyl methyl ester of valsartan can be hydrolyzed with alkali metal hydroxides followed by acidification to give valsartan. This novel process does not use costly hydrogenating catalysts such as palladium-charcoal and is amicable for commercial production.
It is therefore an object of the present invention to provide a cost-effective process for the preparation of valsartan and pharmaceutically acceptable salts thereof, the said process being amicable for commercial production.
